Method for producing 4-hydroxyquinolines



Patented Apr. 18, 1950 METHOD FOR PRODUCING 4-HYDROXY- QUINOLINES Charles 0. Price,

Secretary of War Royston M. F. Herbrandson, Urbana, United States of Ameri Roberts, and Harry Ill., assignors to the ca as represented by the No Drawing. Application June 4, 1945, Serial No. 597,584

, 2 Claims. (or. 260-289) The present invention relates to the preparation of certain quinoline compounds, and more particularly, to a new and improved method of synthesizing certain nuclear substituted quinoline compounds having at least one nuclear substituent in each ring of the quinoline nucleus.

Diand poly-substituted quinoline compounds having at least one substituent in each ring of the quinoline nucleus constitute an important class of intermediates used in the preparation of various industrial and pharmaceutical products. Of this group of-intermediates, the 4-hydroxyquinoline compounds of the type (I) having at least one monovalent nuclear substituent (X) in the carbocyclic ring of the quinoline nucleus ing free acid (VI) and the acid decarboxylated to produce a substituted quinoline compound (VII) of the general type (I). R000 I OH C1 OH a I 01- N I COOR N COOR' V VIII Although the foregoing preparative method is i probably more satisfactorythan any other process heretofore availabe forthesynthesis of compounds of this general type (I), the process in question is nevertheless subject to several serious limitations. Of these, perhaps the most significant arises fromthe-fact that when the process is carried out with a meta substituted aniline compound having two free ortho hydrogen atoms, for instance, with m-chloraniline (II), the product of cyclization is generally a mixture containing substantial proportions of each of the two possible isomers (V and VIII). As a result, the yield of the'desired isomer (e. g., V) is undesirably low, andalthough separation of the isomers is possible, it is nevertheless a laborious and wasteful operation that still further reduces the ultimate yield of the desired compound.

Another disadvantage of this synthetic method arises from the fact that, as a general rule, the 2 carboxy 4 hydroxyquinoline compounds formed as intermediates in this process (e. g., VI) are often diflicult to decarboxylate, and in such instances, the yields in the decarboxylation step are also undesirably low. For these and other reasons, the synthetic methods heretofore available for the preparation of compounds of type (I) leave much to bedesired. I

Broadly speaking, the object of the present invention is to provide a novel synthetic method that obviates the disadvantages of the prior art processes of producing 4-hydroxyquinoline com pounds having at least one monovalent nuclear substituent in the carbocyclic ring of the quinoline nucleus.

A more particular object is the provision of an improved method of producing substituted quinoline compoundssuitable for use as intermediates in thesynthesis of anti-malarials.

Another object is to produce intermediates of the classdescribed, by a process involving a cylization reaction that generally forms a reaction product consisting preponderately of one isomeric compound in those instances where ring closure can theoretically take place in two difierentways with the formation of two isomeric compounds.

Still another object is to produce the above type of intermediate by a process involving the formation of a nuclear substituted 4-hydroxyquinoline carboxylic acid that is readily decarboxylated in high yields to the desired intermediate (I).

A further object is the provision of a new and improved method of producing 4-hydroxyand 4-haloquinoline compounds having a substituent in the 7 position of the quinoline nucleus, by a process that utilizes readily available raw materials, generally avoids the formation of substantial proportions of isomeric by-products and involves a sequence of steps all of which give high state of purity a'S fo'l i l'i'ed.

Other objects and advantages will be apparent as'the invention is hereinafter more particularly! described. a, 1

The foregoing objects may be accomplished in accordance with the process of the presentinvention, which is based" in part pon-mammalian.

under appropriate conditionseacrylicacidesters;

of the type (IX), having (a) in the alpha position, a carbalkoxy group (-COOR), a substituted carbamyl roun- (--CONHR'), or a cyano group (CN);-, and;

(b) in the beta position, a nuclear substituted phenylamino group Y having atleast one ortho hydrogen atom, will react, either in their acrylic ester-iorm flXmor in their isomeric anil form (X), to produce a nuclear substituted 4 hydroxyquinoline3-car- "c'oi'isi'sts predominantly of the corresponding 7-- lsubstituted-i-hydroxyquinoline chnipounm: the

-is'om'eric s-substituted -r-hydmxyqumoline cumpound being present, if at all,-usually in a very minor proportion. The process therefore offers the distinct advantage of producing high yields on a '7-substituted-4-hydroxyquinoline compound that is generally relatively free of contamination with isomeric by-products.

A-iurther advantage of the present invention arises from the-fact that the free quinoline-B- carboXylic-acid's (XII) derivable from the products of cytclizationiil e., the free acids corresponding to the ester,-nitrile or anilide), are readily decarboxylated to the desired intermediate (1). lind eed as a general rule, the 3-carboxy-4-hydroxyquinoline compounds as a class deoarboxylatewith surprising ease; in contrast to the diffimay usually encountered in deca'rboxyla'ting quiholine-3-carboxylic' acids that have" no hy-' droxyl-group 'in' the'4-position';

The substituted acrylic acideste'r's' (IX) or their isomeric" anils= (X) constituting thesta'rtin'g materials' for the process of the present invention may-be pre ared by various methods, depending part on the character of the radical in the alpha position of the-ester residue. Thuswhere thealph'a' group" is a carbalk'oxy radical (i. e., where=Y=-0doR the star-ting materials are readily obtainable by condensation of the appropriate nuclear substituteclaniline (XIII) with an alkoxymethylene'malonic ester (XIV), according tothemethcd described by Claisen in Ann-.- 297, 77 (1897).

The correspondingtype of compounds'where Y' is Wcy'ano radical may be formed in a similar manner from a nuclear substituted aniline (XIII) and an alkoxymethy-lenecyanacetic' ester (XV), according" to the scheme:

substituted carbamyl radical may be prepared by condensingfthe appropriate nuclear substituted aniline (XIII) with orthoformic ester to form the corresponding formamidine (XVI) which may then be treated with malonic ester to produce the anil (XVII) or the isomeric acrylate (XVIII) XVII (a)v Preparation rial is obtained from an alkoxymethylene malonic ester (i. e., where Y equals carbalkoxy in formulaIX), the starting material may be cyclized merely by heating the substantially pure material to a temperature of the order of about 250 C. Cyclization may also be accomplished by similarly heating a solution of the uncyclized ester in a high boiling inert solvent (e. g., diphenyl ether, mineral oil or the like), preferably using roughly one mole of ester per liter of solvent.

In those cases where the starting material consists ofthe alpha-cyanoor alpha-carbanilinoacrylates or their isomeric anils, (i. e., where Y is cyano or carbanilino in formula XI or X), satisfactory yields are obtained by dissolving these materials in a relatively large proportion of high boiling inert solvent (e. g., 0.05 to 0.25 mole of uncyclized product per liter of solvent) and heating the resulting dilute solution to a temperature of the order of about 250 C. In the absence of a solventor heat exchange medium, starting materials of these latter types tend to form tarry reaction products whenheated, whereas in more or less dilute solution in an appropriate amount of neutral solvent, the compounds produce excellent yields of the desired cyclized product in a relatively high state of purity.

The cyclized product is readily converted in high yields to the corresponding free acid (XII). In the case of the quinoline-3-carboxylic esters (Y= --COOR) hydrolysis may be accomplished, for example, by saponification with aqueous alkali followed by acidification of the reaction mixture. In the cases of the quinoline-3-carboxylic acid nitriles and anilides (Y=CN or -CONHR'), hydrolysis may be eifected by refluxing the cyclized products with strong (e. g., 75%) aqueous sulfuric acid.

The decarboxylation step of the present invention is readily acomplished simply by fusing the free carboxylic acid (XII) for a short period until eflervescence ceases. The yields in this step are also generally high (75-95%) and in many cases are nearly quantitative (96-98%).

As an alternative method of decarboxylation, the

free acid (KID-which need not be thoroughly dry--may be suspended in the same solvent that was used in the'cyclizing step (e.g., in diphenyl ether) and the suspension heated until the solid dissolves or. until evolution of carbon dioxide ceases. The decarboxylated product generally crystallizes from the solvent when the reaction mixture cools. The yields obtained in this alternate method are also generally high; i

In order more clearly to disclose the nature of the present invention, severalspecific examples will hereinafter be described in considerable detail. -It should be clearly understood, however, that this is done solely by way of example and not for the purpose of delineating the scope of the invention or ofrestricting the ambit of the appended claims.

' EXAMPLE I PREPARATION or 4,7-DICHLOROQUINOLINE of diethyl ethoxymethylenemalonate 'Ethoxymethylenemalonic ester was prepared from ethyl orthoformate and malonic ester by a slight modification of the original procedure of Claisen (Ann, 297, 75 (1897)), the principal change being the use of a much smaller amount (1. e., a trace) of zinc chloride. Yields on several runs ranged between forty-five and fifty-five per cent of the theoretical.

(1)) Preparation of the anil Equimolecular amounts of m-chloraniline and diethyl ethoxymethylenemalonate were mixed and (a) warmed at 120 C. with stirring for one hour, or (b) allowed to stand in vacuo for six. teen hours while a stream of air was conducted through the mixture by means of a capillary tube. With the first method, there was obtained an oil which solidified on standing but which may be used directly in step c. When the second method was used, the product was obtained as a white crystalline mass. The yields by both methods were practically quantitative.

(c) C'yclz'zation The molten anil was slowly added to three to four times its weight of diphenyl ether or Dowtherm A (a mixture of diphenyl ether and diphenyl) maintained at about 245-250 C. After all the anil had been added the mixture was held at about 245-250" C. for about one hour. An air-cooled condenser was used so that the alcohol produced during cyclization might escape easily. in some cases a rapid stream of nitrogen was led into the mixture by a tube which reached to the bottom of the flask. In other cases, particularly in small (0.1 mole) runs, .no nitrogen was used and the solution was merely refluxed at the boiling point. Some of the cyclized product separated during the heating period, and after cooling, the reaction mixture became practically solid. The cold mixture may be used directly in the next step. Samples isolated from this reaction mixture by filtration and washing with petroleum ether were pure 3-carbethoxy-4- hydroxy-7-chloroquinoline; M. P., 296-298 C. (uncorr.). Yields of up to 96 per cent of the theoretical were obtained in the cyclization step.

(d) Hydrolysis To the cyclization mixture was added 2.5 equivalents of 10 per cent aqueous sodium hydroxide and saponification was allowed to proceed under reflux for from one tothree hours, depending on the size of the run.- (Saponification is complete within thirty minutes for 0.1 mole runs.) The resulting two-phase mixture was separated by siphonation or by means of a separatory funnel and the aqueous layer was washed with ligroin or petroleum ether and filtered. The acid was precipitated with 18 per cent aqueous hydrochloric acid, collected on a filter and thoroughly washed by resuspension in water and refiltration. The acid was then dried in a vacuum oven. Overall yields for the conversion of the ester to the free acid were -95 per cent of the theoretical.

(e) Decarboxylation The thoroughly dried acid washeated in 200 to 300 grams portions to 250-270 (3.; carbon dioxidewas evolved readily as the material melted. The mixture was heated until effervescense ceased (five to ten minutes after completely melted) and then allowed to cool and solidify. The cake was ground up and used directly in the next step. The yield was 98% of the theoretical. As an alternate method of decarboxylation, the

acid (which. need not be. completely dry). may be suspended. in about five times its. weight. of diphenyletherl or Dowtherm A and heatediunder. refluxfor. an hour.. When the solution. was allowed. to. cool to.- roomv temperature, the hydroxy quinoli-ne. crystallized.

(1) Conversion to 4,7*-'dichloroquinoline To 4.4 moles oi? phosphorus oxychloride, heated to 90-100? C. was added 1.7 moles of the decartetn'eyiate6: productin small portions. The mixturewassti -reri during; the additiona d allowed to boil tinder reflux. After the addition was com lete, the excess phosphorus oxychloride was reeoverezipy distillation in vacuo and the residue wa's'adde'd t'o l to 2- liters of ice and water; The resulting soluti n of the hydrochloride was n1- ti'ed and the filtrate neutralized carefully with if) cent aqueous sodium hydroxide to liberate tnefree base. The light tan precipitate wascoliected' on a filter, washed thoroughly ariddried in air at 50 C. for thirty-six hours. Yields of 75-80 per cent 01: the theoretical were obtained.

The conversion may also be carried out on the product obtained in the-second or alternate methd at carrying" oiitstep (3, without separating the product frerri the so1vent; In this case pnes phor't'is' orychlorioe may also be used. The cooled realities mixture is poured into water and: the 4 ,-7=dicliloroqi iinoliiie is extracted with" dilute hydich-ldric acid.

- Permeation of the final product was effected by recrystallization from either methanol or etnanor watermixtures, or byextraction Gfth crudeiriiateriat with low-boiling petroleum ether. The ptirified product; mating at 85'-86- 6;. consisted: of white needles.

'Eitmiasnon' or" ZFCHLOHCY-7*TRIFLUOROME'IPHYL QUINOL-INE ((25 Preparation of (Mill A. mixture. of 16.1. g.. (0.1 mole) of r'n-t'rifiuoroniethylanilihe and 21.6 g. (0.1 mole) of etho'xy methylenemalonie ester was placed in a. filter flask and. suction was. applied froma water pump (ca. 20- iiimo". The contents or the filter flask was kept at 50 C for one and one-half hours. The productwas a light yellow oil which solidified' after standing a day; it melted at 45-46 C. The yield was 33 g. or 90% of the theoretical.

( b) Cycliaation In a' 2'50-=cc. flask was placed 100 cc. of di-. phenyl ether; The solvent was heated to boil ingover an open flame and 16.5 g; (0.05 mole) of the anil was. added 'dropwise from a dropping funnel, over. a period of twenty minutes. When thela'st of the an'il had been added, the product Began to precipitate. The refluxing was continued for another twenty minutes and then stopped. The filtering and washing operations were similar to thoseused in the preparation of dichloro-quinoline; The yield was 12 g. or 85% of the theoretical; M; P., ca. 294 297 C.

(c) Hydrolysis and decarboxylation ,A mixture of 565' g. of the ester and aqueous :sodium. hydroxide was. refluxed for. two

' and one-half. hours and the reaction mixture was.- then acidified. The. yield was 48' g. of the acid or 92% ofrthetheoreticale The. acid. decomposed. at125li Ci. I

In a 1000-0 0; flash. 49.51 g- 0t theireeaeid was heated at 265-270," C; for five. mimitesz. 39 g.- of

4ehydroxy-7-trifluoromethy1r quinoline (92% of the theorietical')"- was obtained; M; R, 268-270- c.

(1%) Conversionto e-ehloro -7--t1=ifluoromethyL quinoltna 4622 g. (0.019 mole) of hosphorus p'er'itah-lo rideandfil-l g. (6.00% mole? of phosphorus oxy chori'de in a" three-necked flask equipped with a stirrer was heated to so 6. T0 this was added 329 g. (0.019 mole?" of the aloove hydroxy compound. The temperature was raised to i0'" C. and heating continued at this temerature for forty minutes. The product was worked up the manner descrited in Example I. The yieldof l cl'iloro fltrifiiioroitiethylquino line was 3.8 g. r of the theoretical; M. P, ii-72 9.

EXAMPLE III PREPARATION on 'l-CHLonoF'T-FLUoRoQUrNeLm.

ta) Prparatima of the; emil' In a, l25 cc'. fiaskwasplaeed' I912 g. (.173 mole) of m.-fiuoroaniiine and 4014 g: L18? mole) of ethoxyniethyleilemalonic ester; The solution was then immersed in an oilliath at C. for forty minutes anrtlie solution was stirred mechani- Cally. Practicallyall or the" ethyl alcohol was evolved during the first ten minutes. The resulting not reaction mixture" was used directly in the subsequent step.

7 (by Gyclizatiow v in a soil-cc; flaskequipped wit-nan air con denser was placed cc. of'di'piienyl ether. The solvent was heated to' reflux and then the and (et mo G1) was added. A slight vacuum was applied at the top of the condenser: After fli t'eeri minutes of vigorous refluxing a white solid began to deposit on th sides of the flask; After a total of one hour of heating, there" was consid eraliile solid on the walls of the flask and very littlealcohol was thereafter evolved. when the contents started to darken; heating was discon tinned, the has; waseooled to room tem erature and 106 cc; of high boiling petroleum ether was added. The solid was broken up and their colleet'er'i in a filter, washed twice with 50-cc. portrons; of high boilingpetroleum ether; and finally dried in an oven at 55* o. The product weighed 395 e. corres onding to 97% of the theoretical.

(0 Hydrolysis The ester from the preceding step was hydrolyZd with 16% aqueoussodium hydroxide and the aeid'litierated as" in Example I. Hydrolysis required only five to ter'iminutes. The product weighed 2911' en, orrespondingto 83.7% of the theoretical: the iinreerystallized material melted at 249-51" C. (uneorr'zi.

(d). Decarboxylation The acid from step (or was dearlioityla-ted in 650: ee'. 61'" dipnenyl etner heated to reflux. A nutty white solid formed during decarboiiylation but this gradually went ihtds''lutiona Heatwas continued. fora total period or about forty-five minutes or until no solid was present.- The de= carboxylatecl prodiietwietied 22' e1, correspondttr a yield or 963% of the theoretical.

(e) Conversion to 4 chloro- 7-fluoroquinoline This compound was'preparedin the-usual manner: using phosphorus pent-achlorlde and phos phorus oxychloride.v Two:- runs gave yields corresponding. to. 62.7% and 70%. oi the. theoretical.

product contained an appreciable proportion of the 5-fluoro isomer.

, EXAMPLE IV PREPARATION or 4,7DICHLOR-5METHOXY- QUINOLINE (a) Preparation of the am'l To prepare the anil, 41.3 g. (.262mole).of 3- amino-5-chloroaniso1e was mixed with 55.1 g.

(0.27 mole) of ethoxymethylenemalonic ester in a 250-cc. Erlenmeyer flask. This mixture was then heated in an oil bath at 110C. for one hour to drive off the ethyl alcohol.

(b) Cyclization 3-carbethoxy-4-hydroxy-5-methoxy '7 chloroquinoline weighed 61.4 g. (0.218 mole), corresponding to an overall yield of 83% of the theoretical based on the amine; M. 2605 C.

(c) Hydrolysis For saponification of the ester, an alcoholwater solution of sodium hydroxide was used; this solution was prepared by dissolving 35 g. (0.37 mole) of solid sodium hydroxide in 325 cc. of 'water. and adding 160 cc. of ethyl alcohol. To

. this solution in a one-liter round-bottomed flask fitted with a reflux condenser was added 61.4 g. (0.218 mole) of the crude ester, After heating the reaction mixture at the boiling point for ten to twelve ,hours, the solution was transferred without cooling to a 3-liter beaker and diluted with water to about 2200 cc. The basic solution was then neutralized by the slow addition of aqueous hydrochloric acid, with vigorous stirring to break into small particles the flocculent precipitate formed and to avoid the formation of a gelatinous mass. The precipitate was collected on a Buchner funnel, and then washed by transferring it to a one literbeaker containing 500 cc. of water, stirring until a homogeneous suspension was obtained and then refiltering. The product was dried at 60 C. for twenty-four hours; the acid weighed 57.4 g. (0.227 mole), correspond- .ing to a nearly quantitative yield; M. P. 255 C.

(d) Decdrboxylation 'to-175 C; and then 57.4 g. (0.227 mole) of 3-carboxy 4-hydroxy-5-methoxy 7 chloroquinoline was slowly added. Any water still present in the acid was driven off. The flask was then fitted with a reflux condenser and the temperature raised to the boiling point. After heating for three-quarters of an hour, nearly all the solid was dissolved. Thehot solution was immediately filtered through a previously heated Buchner Lfunnel. On cooling, the 4-hydroxy-5-methoxy- 7-chloroquinoline separated. Approximately 100 cc. .of high boiling petroleum ether was added to the cooled diphenyl ether, the precipitated solid removed by filtration, washed with high boiling petroleum ether and dried. There was obtained 39.6 g. (0.1895 mole) of the decarboxylated product corresponding to a yield of 83.5% of the theoreical. The melting point of the crude product was 240-50 C.

(e) Conversion to 4,7-dichZoro-5-methoryquinoline In a 500-cc., three-necked, round-bottomed flask equipped with mechanical stirrer and reflux condenser was placed 42.5 g. (0.204 mole) of phosphorus pentachloride and 52.2 g. (0.34 mole) of phosphorus oxychloride. The flask was placed in a steam bath and heated to C. Then, by as rapid addition as possible, 39.6 g. (0.190 mole) of the above crude hydroxyquinoline was introduced. After complete addition, the temperature was elevated to 130 C'. and maintained there for thirty minutes. The excess phosphorus oxychloride was then removed by setting the reflux condenser for downward distillation and distilling until no more came over. The brown sticky product was dissolved by the addition of cc. of cold water and the resulting brown solution was treated once with charcoal (Darco) cooled; and then neutralized with 10% aqueous sodium hydroxide. The crude product when filtered and dried weighed 32.2 g. (0.142 mole), a yield of 74.5%. The recrystallized product weighed 21.2 g. (0.090 mole) or 50% of the theoretical; M. P. 134 C.

EXAMPLE V PREPARATION or 4-HYnRoxY-6-MErHoxYQnINoLINE (a) Formation of anil b) Cyclzzation Cycli-zation was readily effected according to the general procedure described for the corresponding step in Example I. On several one tenth mole runs, the amount of diphenyl ether used was varied within wide limits. Mineral oil .(Stanolind) was also used asa solvent. The maximum yield (ca. 50%) was obtained from mineral oil.

(0) Hydrolysis and decarboxylation Hydrolysis of the ethyl ester and decarboxylation of the acid take place under conditions similar to those described for the corresponding steps'in Example I.

EXAMPLE VI 'PREBARATION or 4,7-DIcHLoRo-6-MErHoxY- QUINOLINE (0) Preparation of the anil when the reaction mixture was cooled.

(b) Cyclization H The anil, heated to a temperature of 100-120 C., was added to 3 to 4 times its weight of diphenyl ether maintained at 250 C. By vigor- :ously refluxing the diphenyl either, solution, the reaction can becompleted. within thirty to iortydive minutes iThje melting point ff the product was. 304'304.5 Q, (u n corr., unrecrystq). The yield was about 82-10075; 7 7 V (*c) Hydrolysis The usual procedurewas-employed using 10% aqueous sodium hydroxide. Hydrolysis was com- ;plete in two and one-half to three hours. The acid 'obtainedgby acidification becoine's slimy when placed in water, The 'unrecrystallized eproduct;meltedatQiSS- lf C. (with decarboxylatio n unrecryst:) tative. v 21) D'c'arbofsylatioafio 4-ayaroxy-6 memory-rv emeraqamozme netgjibbxyuadh wa's carried 'out'b'y refluiiing a difihenyl e er solution of the "senior-t ree ihour's :S'onie q oihposmo iatofbrevm insoluilgle, {5611a "pc'currea, '"es'pciauy 'wh''n flalrg'e runs a rridout. Longer'periodsoffiheating also l qaused seine decomposition into unldesirable-iriatei ial, Theiiirofdufctrneltd' at 241-3? 0 (r'eeryst. crice irto'in alcohol and water), The yield in s'rna llscale runsavera'ged about '74'% andin1arge s'cale runs; about 58.5

"(e) borwersion to 4',7 dz'ch-loro-6 methoa:yqaiao- Zine I The usual procedure was used. The final prdduct did not dissol'i/e 'c-ompl'etely when poured into ice:waterand-sconcentrated aqueous hydrochloric acid was added to efiect cornplete solution. The product crystallized rudely from ethyl alcohol; M. R, -162 "(uncorrzr ="-I1ie -yield was ab'out '75 82'% of the theoretical. EXAMPLE surnames 6F am s-6H :emoseswsmm "("a") i rpafation of in'a yineiliyzeaeegyaaoacac V ester M compound"iastnrepared essentially accofdii xg to "the ip ocedure of aeBsument, 7 Bull. Ste .j-('3 25,1'20 (-1901 The t fal'cetate "wa ren oyedby continuous di'stillatioh an mo- "150 C.-, "after 7 which "the a" eueacid and excess sbegic immens were removed at 'the water ...E "avers-gesment obtained a yield of product was distilled. V I

(b) Preparation of the acrylate ue was recrystallized to g ive an 52- per' aem ror' two runs, D'eBbll- 47 per cent when the of m-chloroaniline for one hour. 'Ethyl alcohol distilled during the; first half-hour. The ring closure was ordinarily carried out on theunpurified '-ethyl 2 eyano 3-'(m-chloraiiilino) acrylate thus obtainedfbutan"analytical sample was recrystallizedfrom 95: ."per sem -alcohol as white -need1es; M. B, 126.5 to 127.5 C.

(C)" Cy'clz'atzdn It was found that it thering closure were carriedout indiphenyl ether at the concentrations ordinarily used with the rnalonates (ca. 1 mole/liter) tarry reaction products "resulted. However, with ten tiniesthis dilution (i. e., about 051 mole of acrylate/liter of diphenyl 'ethery the "cyclizedproduct began to separate from the-boiling '-adi'phenyl eth'er-;after'- the rnixture was; refluxed for about two hours. A 60 per cent yield The yield was nearlyquantix 112. t a of produt; was obtained when the solution was grefluxedf four hours, and 30 per s mester Ifiv'e hours. A run in which 0.2 mole-of the acrylate for six hours gavea 36i5' per cent yield of cyclized product. 7 This cyclized ":pr0duot,;3-cy ano 4-hydroxy-Y-chloroquinoline, .crystallized from the diphenyl etherin tan flakes, M. P ea. 360-370 C. Ananalytical sample maybe prepared by "summation. V

(d) EK/211 23117822? i Ihifteen and six-tenths grams o f'"3-cyano- 4- hydroiiy l-cliloroquiholihej'wasrefluxed with"200 g. arena, "sulfuric acidfor one' hour. fAfter cool- 5 ing the solution, thetan crystals which separated were removed by 'filtration through a sintered- @glas sfunnel. The solid was dis solvediinidilute -;all;a1i, treated with charcoal, and L reprecipitated {-w hacidi to iue white 4 h ydroxy'-'7-cliloroquinoline-3-oarhoxylic acid M. P1270 2" "0. (with decarboxylation), ield 12?? g. Therfiltra tejmade allgaline, treated with =charcoal, and f'then'. neu- Permanence e' nrsaosw q enrosoeumonms lization; M. P. 11641??- C.

(b) Preparation of the acrylate iphenylcformamidine ar id Lmalonic Hester -=were liheate'd to l50+165 vfor "two :hours. The l"'-=-o'arbethoxy 2 -2=(m-'chloranilino) -acryl o-mechlor'ani-lide v was obtained as finewwhite needles in '70 meracentli yield: .af ten onevrecrystallization;

r ins-114 c.

(EV-Cafliziztion yWhen the-ring; closure 56f the acrlvlate lwas carri ed out --with the-concentrations generally wusedior ring closurepf the malonates; tarrylrev action productss-resulted. ,sHowever, with Lten timesthedilution (i e using about .arlmqie 6f eacrylate to; l literot dipheni l l ether) and'lthree =;hours -of;reflu ;i ng, light browniilates crystallized '75 on cooling. The m-chlo'rafiilide'Ejf4' -hydroxy- -13 '7-chloroquinoline-3-carboxylic acid thus obtained melted at 320-322 C. after recrystallization. The yield was 58% of the theoretical. When cyclization was carried out at twice this dilution, the yield was 75%.

(d) Hydrolysis L T e: anilideiwas hydrolyzed to 4-hydroxy- 7-chloroquinoline-3-carboxylic acid by refluxing the former for five minutes in 75% sulfuric acid.

(9) Deccrbomylat ion parent that the basic principles of the present invention may be applied to the preparation of many compounds other than those herein specifically characterized. Thus for example, the following interesting types 01 compounds may be prepared from the starting materials indicated:

from

from

NIH NH:

ill-COC CHI- OH from .from.

- V IHg-O 000m. from Many other applications of the principles of the present invention will be readily apparent to those skilled in the art. All such variations, modifications and extensions of the principles of present inventions are to be understood as embraced within the scope of the appended claims. In connection with this application, reference may be made to the copending applications of Harold R. Snyder and Robert E. Jones, Ser. Nos. 597,586 and 597,587, now Patent No. 2,504,896, both filed June 4, 1945.

Having thus described our invention, what we claim as new and wish to secure by Letters Patent is:

1. In the. preparation of nuclear substituted 4- hydroxyquinoline compounds, the improvement which comprises heating to a temperature sufiicient to efiect ring-closure, a compound selected from the group consisting of the substituted acrylates and the corresponding isomeric anils having the general formulae N:OH.CH(C 0 OR):

where X is at least one halo radical and R is an alkyl radical, by heating a solution of the said compound in a high-boiling, inert solvent consisting principally of diphenyl ether, converting the resulting cyclized product by hydrolysis to the corresponding substituted 4-hydroxyquinoline-3- carboxylic acid, and then heating the said acid to a temperature sufiicient to decarboxylate the same, to produce a compound having the general formula where X is at least one halo radical.

2. In the preparation of nuclear substituted 4- hydroxyquinoline compounds, the improvement which comprises heating to a temperature sumwhere n- 1s at Ie'as'ton'e lia'lb radical;

new

f5 cient to effect ring-closure, a compound selected from the group consisting "of the substituted acrylates and the corresponding isomeric anils having the general formulae CHARLES. 0. PRICE. v 'RoYsTorrM BfoBERfi'sg r HK'RRYTS HERBRANDSGNi REFERENGES CITED Number Number UNITED STA a GTHER; 'REFERENGES uusa-Berithte, v61. i9; p1; 1462 146? and ran th s craze). 

1. IN THE PREPARATION OF NUCLEAR SUBSTITUTED 4HYDROXYQUINOLINE COMPOUNDS, THE IMPROVEMENT WHICH COMPRISES HEATING TO A TEMPERATURE SUFFICIENT TO EFFECT RING-CLOSURE, A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE SUBSTITUTED ACRYLATES AND THE CORRESPONDING ISOMERIC ANILS HAVING THE GENERAL FORMULAE. 